The modification of generally inert solids with gas-phase radicals such as atomic oxygen and hydroxyl radicals is known in the art. In earlier U.S. Pat. Nos. 5,141,806 and 5,215,790, both to Steven L. Koontz, there is disclosed a microporous structure with layered interstitial surface treatments, which is prepared by sequentially subjecting a uniformly pore-surface-treated porous structure to atomic oxygen treatment to remove an outer layer of pore surface treatment to a generally uniform depth within the porous solid, and surface treating the so oxidized region of the porous solid with another surface treating agent. The atomic oxygen/surface treatment steps can be repeated, each successive time to a lesser depth within the porous solid, to produce a microporous structure having multi-layered pore surface chemistries. This structure and preparation methodology are disclosed primarily for use with porous substrate structures which are inert in oxidizing plasmas, such as refractory metal oxides like alumina or silica. The surface treating agents are primarily organic compounds which are reactive with atomic oxygen plasma so they can be removed by exposure thereto.
In our copending application U.S. Ser. No. 07/857,901, filed Mar. 26, 1992, by Koontz, Spaulding and Leger, now U.S. Pat. No. 5,369,012 a method for making a biocompatible polymer article using a uniform atomic oxygen treatment of a polymer substrate is disclosed. The substrate may be subsequently optionally grafted with a compatibilizing compound, such as proteins, phosphorylcholine groups, platelet adhesion preventing polymers, albumin, adhesion promoters, and the like. The compatibilized substrate may also have a living cell layer adhered thereto. Also disclosed are a vascular prosthesis and other articles made by the biocompatibilizing method as well as methods for using such biocompatibilized articles in a cell mass. In addition, membranes made by the biocompatibilizing method are disclosed, and methods for performing immunodiagnostic testing using the membranes. Also, methods for culturing cells for various purposes using the various membranes are disclosed.
The use of polymeric materials for biomedical implants and in biotechnical manufacture is an advancing art. Plasma discharges have been used to engineer such polymers because surface chemistry can be altered without adversely affecting bulk properties which make polymeric materials useful. However, plasma devices typically do not deliver a uniform concentration of the reactive species. Subject to complex interactions, non-uniform distribution of plasma species may increase manufacturing difficulty and impair quality control.
Silicone rubber has long been used in medical devices such as surgical implants due to desirable properties including gas permeability, pliability, degradation resistance, ease of fabrication and relatively good biocompatibility. However, such materials are not completely inert in the body. Recent methods have been sought to improve its biologic inertness by either surface modification to increase hydrophilicity or bulk modification, i.e. incorporating polar groups into the monomer or prepolymer. Tsai, Chi-Chun et al., in Transactions of the American Society of Artificial Internal Organs (ASAIO), vol. XXXIV, (1988) discloses a method for increasing the albumin affinity of silicone rubber. A vinyl-methyl silicone comonomer was hydroxylated and then film coated on a silicone rubber sheet. The OH-coated sheet was grafted with a C.sub.16 alkyl chain having a terminal acyl group by an esterification reaction catalyzed by 4-dimethylaminopyridine. Albumin adsorption and retention was said to be markedly enhanced for surface OH and C.sub.16 concentrations as low as 5% reaction yield. Tsai, Chi-Chun et al., in ASAIO, vol. XXXVI, (1990) discloses use of the above albumin adsorbed silicone surfaces as thin transparent, biocompatible films for coating the surfaces of blood contacting devices. These films are said to retard undesired responses, e.g. blood coagulation and activation of complement proteins, platelets and white blood cells, triggered by exposure of blood stream macromolecules to a foreign surface.
Polymer prostheses have been considered for vascular applications. C. Stimpson et al., in Biomaterials, Artificial Cells, and Artificial Organs, 17(1), (1989), pp. 31-43 discloses silicone rubber canine aortic prostheses. A uniformly microporous prosthesis is made by molding the polymer in a template taken from the skeletal structure of a marine life form.
Durrani et al., in Polymer Surfaces and Interfaces, chapter 10, J. Wiley & Sons, (1987), pages 189-200 discloses modification of polymer surfaces with a phosphorylcholine, for example, to mimic biomembrane surfaces in bioapplications. Modifications of this sort are said to reduce foreign surface induced thromboses associated with the use of blood contacting devices.
Rajender Sipehia in Biomaterials, Artificial Cells, and Artificial Organs, 16(5), (1988-89), pp. 955-966 discloses immobilizing proteins to polymeric surfaces. Polypropylene membranes are treated by gaseous oxygen or ammonia plasma to add hydroxyl or amino groups to the polymer surface. The proteins are then grafted to the surface. Rajender Sipehia in Biomaterials, Artificial Cells, and Artificial Organs, 18(3), (1990), pp. 437-446 discloses ammonia plasma modification of polystyrene petri dishes and poly(tetrafluoroethylene) membranes and grafting of proteins to the surface. The growth of bovine pulmonary artery endothelial cells on the modified surface is enhanced by adherence to the grafted proteins.
In U.S. Pat. No. 4,134,949 to Chen, the surface of a contact lens is modified by deposition of a hydrophilic polymer under the influence of plasma glow discharge to integrally bond the coating to the surface of a hydrophobic lens.
Elizabeth G. Nabel et al., in Science, vol. 244, Jun. 16, 1989, pp. 1342-1345 discloses a transplant of endothelial cells expressing a recombinant gene into an arterial wall. The transplanted cells may contribute to altering the thrombic properties of the vessel lumen by inducing smooth muscle cell proliferation and regulating smooth muscle cell tone. In addition, genetically altered cells could transmit recombinant DNA products.
Polymer surfaces have been modified by plasma application to prepare membranes for dialysis and ultrafiltration. Hiroo Iwata et al. in Journal of Membrane Science, vol. 38, (1988), pp. 185-189 discloses a macroporous poly(vinylidene fluoride) membrane pretreated by air plasma and subsequent graft polymerization of hydrophilic monomers on the treated surface. Such membranes are said to be environment-sensitive and can be used to mimic biological membranes or in a closed-loop drug delivery system. J. Wolff, Journal of Membrane Science, vol. 36, (1988), pp. 207-214; F. Vigo et al., Journal of Membrane Science, vol. 36, (1988), pp. 187-199; F. F. Stengaard, Journal of Membrane Science, vol. 36, (1988), pp. 257-275; and Fang Yuee et al., Journal of Membrane Science, vol. 39, (1988), pp. 1-9 disclose the preparation of a variety of dialysis and ultrafiltration membranes.
Various polymers have been modified by plasma processes to alter surface chemistry, adhesion properties, and the like. See H. K. Yasuda et al., Polymer Surfaces and Interfaces, chapter 8, J. Wiley & Sons, (1987), pages 149-162.